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Maternal Thrombosis and Link to Thrombophilia


 

Inherited thrombophilia and its association with both maternal thrombosis and adverse pregnancy outcomes is an issue that has come to the forefront over the past few years.

The association between inherited thrombophilia and maternal thrombosis appears to be fairly robust. Collectively, these thrombophilias account for 50%-70% of all maternal venous thrombotic events in pregnancy. Knowledge of the thrombophilic status of a patient can, therefore, have a significant impact on her clinical care. We understand better today, however, that personal and family history plays a critical role in assessing maternal thrombotic risk.

By contrast, the precise nature of the link between inherited thrombophilia and adverse pregnancy outcomes is still unclear. Over the past decade, the number of negative reports—those showing a lack of association—has increased significantly, and multiple prospective cohort studies have failed to consistently demonstrate the associations suggested by prior case-control studies that were smaller and mainly retrospective.

Collectively, this new landscape of research findings suggests that we should stop screening for inherited thrombophilia in patients with adverse pregnancy outcomes except in the setting of institutional review board–approved studies, and that we should better focus our approach to preventing maternal thrombosis through more careful, individualized risk assessment and through targeted use of antithrombotic therapy.

A New Evidence Base

Initial reports of associations between inherited thrombophilia and adverse pregnancy outcomes such as fetal loss, preeclampsia, fetal growth restriction, and abruptio placentae made some biological sense, but were based largely on small retrospective case-control studies with often inconsistent or contradictory findings.

In the case of fetal loss, numerous studies published in the 1990s and into the next decade showed a moderate association between inherited thrombophilia and stillbirth in particular.

A European retrospective cohort study published in 1996, for instance, found that the increased risk of loss among women with thrombophilia was greater after 28 weeks (odds ratio 3.6) than at or before 28 weeks (OR 1.4), and that the highest risk for stillbirth was associated with combined thrombophilic defects and antithrombin and protein C deficiencies (Lancet 1996;348:913-6).

This confusingly named study—the European Prospective Cohort on Thrombophilia (EPCOT)—involved 571 women with thrombophilia having 1,524 pregnancies, and 395 controls having 1,019 pregnancies.

In 2005, investigators of a larger case-control study nested within the 32,683-patient Nimes Obstetricians and Haematologist cohort reported an association between the factor V Leiden (FVL) mutation and pregnancy loss after 10 weeks (OR 3.5) but not between 3 and 9 weeks (J. Thromb. Haemost. 2005;3:2178-84)

A retrospective cohort study published in 2004 of 491 patients with a history of adverse pregnancy outcomes suggested, moreover, that one or more thrombophilia were actually protective of recurrent fetal losses at less than 10 weeks (Thromb. Haemost. 2004;91:290-5). However, the association of any one thrombophilia with later fetal losses was less significant in this study than in other studies (OR 1.76).

And an earlier meta-analysis of 31 studies looking at fetal loss and various thrombophilic disorders (most of them small case-control studies) concluded that FVL was associated with first-trimester pregnancy loss (OR 2.0) as well as later loss, although the association was much stronger (OR 3.3) with late, nonrecurrent fetal loss (Lancet 2003;361:901-8).

Although these and other studies suggested a link between FVL and stillbirth (and perhaps other thrombophilias and stillbirth), the absolute magnitude of the association (i.e., the absolute risk) was still very small. Moreover, over the past decade, the number of negative reports, especially amongst prospective studies, has increased—a temporal dichotomy that strongly suggests an initial bias toward positive studies and a growing comfort in reporting negative studies.

The larger prospective cohort studies reported over the last 5 years or so enerally have not found an association between inherited thrombophilia and stillbirth—or other adverse pregnancy outcomes for that matter.

For example, a 2005 study conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Maternal-Fetal Medicine Units Network identified 134 FVL mutation carriers among nearly 4,900 gravidas in their first trimester of pregnancy and found no increase in fetal loss, preeclampsia, abruption, or intrauterine growth retardation (IUGR). A secondary analysis these data published earlier this year similarly found no association between the prothrombin gene G20210A mutation (PGM) and adverse pregnancy outcomes (Obstet. Gynecol. 2005;106:517-24 and Obstet. Gynecol. 2010;115:14-20).

Another prospective study of 4,250 unselected pregnancies also found no significant associations between FVL and preeclampsia, IUGR, and pregnancy loss (Br. J. Haematol. 2008;140:236-40).

Some of these findings are similar to previous reports from smaller prospective cohort studies. Investigators reported in 1999, for instance, no association between activated protein C resistance and fetal loss, preeclampsia, and IUGR. And in 2000, investigators had similarly reported a lack of association between FVL and methylenetetrahydrofolate reductase (MTHFR) polymorphism and preeclampsia or IUGR.

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